The Purpose of this Center proposal is to bring to bring together three research groups of senior investigators with long, highly successful track records, to focus on defining the cellular, biochemical and molecular genetic pathology which contributes to the affective dysregulation observed at depressive illness. Innovative technology will be utilized by each group. This will represent a massive, concentrated effort in that each research team will use brain tissue from the same group of depressed patients and matched controls. There is broad consensus that depressive illness is associated with a strong genetic component, a dysregulation of the HPA axis and alterations in serotonin metabolism and physiology. In addition, a body of emerging data including that from brain imaging studies show that a subgroup of depressed patients have increased ventricular size, hypofrontality, plus other neuropathological findings similar to those observations that led to the neurodevelopmental hypothesis of schizophrenia. The specific hypothesis to be explored is that there is a genetic or epigenetic associated neurodevelopmental abnormality in one or more brain structures that have been repeatedly implicated in depressive illness [frontal cortex, anterior cingulate gyrus, raphe, locus coeruleus, paraventricular nucleus (PVN) of the hypothalamus, the hippocampus, and the raphe nuclei.] Methods to be utilized will include immunohistochemistry, in situ hybridization, and microarray DNA chip technologies. It is anticipated that the study of molecules associated with LHPA stress axis, the 5HT system and neuronal migration will suggest potentially productive foci on specific brain regions and genes to be investigated in association with the microarray chip technology. We theorize that assessing the levels and expression patterns of thousands of genes from a number of multiple sites in the regions listed above will allow us to identify a consistent pattern of dysregulation in the brains of depressed patients.